Reversal of Chronic Molecular and Cellular Abnormalities Due to Heart Failure by Passive Mechanical Ventricular Containment

Sabbah, Hani N.; Sharov, Victor G.; Gupta, Ramesh C.; Mishra, Sudhish; Rastogi, Sharad; Undrovinas, A. I.; Chaudhry, Pervaiz A; Todor, Anastassia; Mishima, Takayuki; Tanhehco, Elaine J.; Suzuki, George

doi:10.1161/01.res.0000101932.70443.fe

Cited by 102 publications

(90 citation statements)

References 49 publications

(78 reference statements)

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“…The observed functional benefit corroborates previous studies including ours showing a reduced LV dilatation and stabilized cardiac function when biomaterials such as porous, solvent-casted or particle leached substrates of poly(glyocolic-co-caprolactone), poly(lactic-co-caprolactone) or polyurethane hydrogel matrices were implanted together with MSCs [9,10,[48][49][50] or skeletal myoblasts [4,51].The main advantages of the current patch design rely on its mechanical integrity and its very thin nature necessary for an adequate positioning on the beating heart that remained stable for at least 4 weeks. Furthermore, characteristics of our matrix, such as a versatile and cost-efficient production and functionalization technology, as well as high potential for custom-tailored and tissue-specific modification, guarantee straightforward scaling up of the biograft.…”

Section: Discussionsupporting

confidence: 89%

Plasma-functionalized electrospun matrix for biograft development and cardiac function stabilization

et al. 2014

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Cardiac tissue engineering approaches can deliver large numbers of cells to the damaged myocardium and have thus increasingly been considered as a possible curative treatment to counteract the high prevalence of progressive heart failure after myocardial infarction (MI). Optimal scaffold architecture and mechanical and chemical properties, as well as immune-and bio-compatibility, need to be addressed. We demonstrated that radio-frequency plasma surface functionalized electrospun poly (e-caprolactone) (PCL) fibres provide a suitable matrix for bone-marrow-derived mesenchymal stem cell (MSC) cardiac implantation. Using a rat model of chronic MI, we showed that MSC-seeded plasma-coated PCL grafts stabilized cardiac function and attenuated dilatation. Significant relative decreases of 13% of the ejection fraction (EF) and 15% of the fractional shortening (FS) were observed in sham treated animals; respective decreases of 20% and 25% were measured 4 weeks after acellular patch implantation, whereas a steadied function was observed 4 weeks after MSC-patch implantation (relative decreases of 6% for both EF and FS).

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Section: Discussionsupporting

confidence: 89%

Plasma-functionalized electrospun matrix for biograft development and cardiac function stabilization

et al. 2014

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“…The present study demonstrates that long-term monotherapy with high-dose but low-dose selective MMP inhibitor PG-530742 prevents progressive LV dysfunction and LV chamber remodeling in dogs with moderate HF. The effects seen with the high dose are modest but in line with studies done earlier with ␤-blockers, eplerenone, and devices in this model of HF in dogs (19,20,24). The beneficial effects of high-dose PG-530742 are consistent with the observation that at this dose and not the low-dose mRNA, the expression of MMP-2, -3, -9, and -13 decreased compared with placebo-treated HF dogs.…”

Section: Discussionsupporting

confidence: 88%

Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure

Morita¹,

Khanal²,

Rastogi³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure. Am J Physiol Heart Circ Physiol 290: H2522-H2527, 2006. First published January 20, 2006 doi:10.1152/ajpheart.00932.2005 contribute to the progression of left ventricular (LV) dysfunction and remodeling associated with heart failure (HF). The present study examined the long-term effects of a selective MMP inhibitor PG-530742 (PG) on the progression of LV dysfunction and remodeling in dogs with HF. Chronic HF [LV ejection fraction (LVEF), Յ36%] was produced by multiple sequential intracoronary microembolizations in 24 dogs. Two weeks after the last embolization, dogs were randomized to 3 mo of therapy with either high-dose (HD) PG (3.5 mg/kg, n ϭ 8), low-dose (LD) PG (0.2 mg/kg, n ϭ 8), or to a matched placebo (PL, n ϭ 8). PG has been shown to produce complete inhibition of MMP-2, -3, -9, and -13, while sparing MMPs-1 and -7. Hemodynamic and echocardiographic measurements were made before and 3 mo after initiating therapy. In PL and LD dogs, LVEF decreased significantly, and LV end-systolic volume (ESV) and LV end-diastolic volume (EDV) increased significantly during the 3-mo follow-up period. Whereas in HD dogs ejection fraction increased from 36 Ϯ 1 to 40 Ϯ 1% (P ϭ 0.003), EDV and ESV decreased (59 Ϯ 4 vs. 57 Ϯ 4 ml, P ϭ 0.02; and 38 Ϯ 2 vs. 34 Ϯ 2 ml, P ϭ 0.00001, respectively). When compared with controls, HD-treated dogs showed 30% reduction in replacement fibrosis, 29% reduction in interstitial fibrosis, and 28% reduction in myocyte cross-sectional area. mRNA expression of selective MMPs was also reduced in LV tissue in HD-but not LD-treated dogs. In conclusion, in dogs with moderate HF, long-term monotherapy with HD selective MMP inhibitor PG prevents LV remodeling and the progression of global LV dysfunction.hemodynamics; PG-530742; left ventricular ejection fraction THE BALANCE BETWEEN extracellular matrix synthesis and degradation has been considered to play a key role in maintaining left ventricular (LV) geometry and function. The extracellular matrix provides structural support for myocyte alignment and blood vessels (26,27). It also coordinates the conversion of myocyte contraction into myocardial force. Furthermore, it can affect myocardial stiffness and diastolic function (26,27).Matrix metalloproteinases (MMPs) are enzymes responsible for proteolytic degradation of specific extracellular matrix components. MMPs are synthesized as inactive zymogens and secreted into the extracellular space. MMPs have been shown to be involved in a variety of pathological and healing processes, such as tumor growth and metastasis, rheumatoid arthritis, and periodontal disease. In the cardiovascular field, it is now becoming clear that extracellular matrix degradation is involved in the pathogenesis of atherosclerosis, restenosis, dilated cardiomyopathy, and myocardial infarction.Expression and activity of MMPs are elevated in both patients and experimental animal mo...

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“…Other pharmacological interventions that may attenuate local inflammatory pathways such as statins have also been demonstrated to modify MMP levels (171,461). Finally, modifying myocardial mechanical load has also been shown to reduce the pattern and magnitude of MMP levels within the remodeling myocardium (31,206,230,375). As detailed previously, LV unloading in DCM patients by mechanical assist reduced myocardial MMP levels (206,230).…”

Section: Therapeutic Interventions Affecting Mmp Induction/activationmentioning

confidence: 75%

“…As detailed previously, LV unloading in DCM patients by mechanical assist reduced myocardial MMP levels (206,230). With the use of a passive myocardial restraint device, myocardial MMP levels have been altered in animal models of MI and ischemic DCM (31,375). Taken together, the therapeutic armamentarium that is currently available for patients with LV remodeling, as well as emerging therapies, are likely to have effects on critical MMP transcriptional pathways.…”

Section: Therapeutic Interventions Affecting Mmp Induction/activationmentioning

confidence: 85%

“…In ischemic DCM, large areas of ECM accumulation, that is, focal areas of myocardial fibrosis, are accompanied by other areas of the myocardium in which ECM content and composition are reduced. For example, in an animal model of ischemic DCM created by repeated coronary embolizations, areas of collagen accumulation are accompanied by localized areas of collagen loss (156,375). Thus a heterogeneous pattern of ECM remodeling occurs in ischemic DCM where enhanced ECM accumulation and degradation occur simultaneously.…”

Section: Myocardial Remodeling In Cardiomyopathic Diseasementioning

confidence: 99%

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Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

Spinale¹

2007

Physiological Reviews

1,004

1,023

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It is now becoming apparent that dynamic changes occur within the interstitium that directly contribute to adverse myocardial remodeling following myocardial infarction (MI), with hypertensive heart disease and with intrinsic myocardial disease such as cardiomyopathy. Furthermore, a family of matrix proteases, the matrix metalloproteinases (MMPs) and the tissue inhibitors of MMPs (TIMPs), has been recognized to play an important role in matrix remodeling in these cardiac disease states. The purpose of this review is fivefold: 1) to examine and redefine the myocardial matrix as a critical and dynamic entity with respect to the remodeling process encountered with MI, hypertension, or cardiomyopathic disease; 2) present the remarkable progress that has been made with respect to MMP/TIMP biology and how it relates to myocardial matrix remodeling; 3) to evaluate critical translational/clinical studies that have provided a cause-effect relationship between alterations in MMP/TIMP regulation and myocardial matrix remodeling; 4) to provide a critical review and analysis of current diagnostic, prognostic, and pharmacological approaches that utilized our basic understanding of MMP/TIMPs in the context of cardiac disease; and 5) most importantly, to dispel the historical belief that the myocardial matrix is a passive structure and supplant this belief that the regulation of matrix protease pathways such as the MMPs and TIMPs will likely yield a new avenue of diagnostic and therapeutic strategies for myocardial remodeling and the progression to heart failure.

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Reversal of Chronic Molecular and Cellular Abnormalities Due to Heart Failure by Passive Mechanical Ventricular Containment

Cited by 102 publications

References 49 publications

Plasma-functionalized electrospun matrix for biograft development and cardiac function stabilization

Plasma-functionalized electrospun matrix for biograft development and cardiac function stabilization

Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart failure

Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function

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